2002
INFLUENZA VIRUS
INFLUENZA VIRUS
CDC WEBSITE
http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm
1
‘FLU’
• True influenza
– influenza virus A or influenza virus B (or
influenza virus C infections - much milder)
• Febrile respiratory disease with
systemic symptoms caused by a variety
of other organisms often called ‘flu’
2
South Carolina 1996-1997 DHEC bulletin
malathia influenzae per le stelle
no virus
CULTURE
RESULTS
influenza A
influenza B
3
http://www.state.sc.us/dhec/LAB/labbu017.htm
THE IMPACT OF INFLUENZA
PANDEMICS
Deaths:
1918-19 Spanish flu 500,000 US
20,000,000 world
1957-58 Asian flu
70,000 US
1968-69 Hong Kong 34,000 US
flu
4
THE IMPACT OF INFLUENZA
• 1972-1994 (19 influenza seasons)
– >20,000 US deaths in 11 seasons
– >40,000 US deaths in 6 of these
– many more hospitalizations (~110,000 per
year)
5
THE IMPACT OF INFLUENZA
• recently some increase in morbidity and
mortality - possible factors?
– more elderly people
– CF patients live longer
– more high risk neonates
– more immunosuppressed patients
6
ORTHOMYXOVIRUSES
• pleomorphic
• influenza types A,B,C
• febrile, respiratory
illness with systemic
symptoms
http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html
7
ORTHOMYXOVIRUSES
HA - hemagglutinin
NA - neuraminidase
helical nucleocapsid (RNA plus
NP protein)
lipid bilayer membrane
polymerase complex
M1 protein
type A, B, C : NP, M1 protein
sub-types: HA or NA protein
8
TRANSMISSION
• AEROSOL
– 100,000 TO
1,000,000 VIRIONS
PER DROPLET
• 18-72 HR
INCUBATION
• SHEDDING
9
NORMAL TRACHEAL MUCOSA
3 DAYS POST-INFECTION
7 DAYS POST-INFECTION
10
Lycke and Norrby Textbook of Medical Virology 1983
• DECREASED
CLEARANCE
• RISK BACTERIAL
INFECTION
• VIREMIA RARE
11
Lycke and Norrby Textbook of Medical Virology 1983
RECOVERY
• INTERFERON - SIDE EFFECTS
INCLUDE:
– FEVER, MYALGIA, FATIGUE, MALAISE
• CELL-MEDIATED IMMUNE RESPONSE
• TISSUE REPAIR
– CAN TAKE SOME TIME
12
An immunological diversion
INTERFERON
13
INTERFERON
timecourse of virus production will vary from virus to virus
14
INTERFERON
15
INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
16
INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
17
INTERFERON
antiviral state
antiviral state
antiviral state
antiviral state
18
INTERFERON
THE VIRUSES ARE COMING!
PAUL REVERE
http://www.mfa.org/collections/one_hour/6.htm
19
http://www.paulreverehouse.org/midnight.html
TYPES OF INTERFERON
• TYPE I
•Interferon-alpha (leukocyte interferon, about 20
related proteins)
- leukocytes, etc
•Interferon-beta (fibroblast interferon)
- fibroblasts, epithelial cells, etc
•TYPE II
•Interferon-gamma (immune interferon)
- certain activated T-cells, NK cells
20
INDUCTION OF INTERFERON
•interferon-alpha and interferon-beta
- viral infection (especially RNA viruses), double
stranded RNA, certain bacterial components
- strong anti-viral properties
•interferon-gamma
- antigens, mitogenic stimulation lymphocytes
21
INTERFERON
• induce various proteins in target cells
• many consequences, not all fully
understood
22
INTERFERON-ALPHA AND
INTERFERON-BETA
23
interferon-alpha, interferon-beta
interferon receptor
induction of
2’5’oligo A synthase
ds RNA
induction of
ribonuclease L
2’5’oligo A
activated
2’5’oligo A synthase
activated
ribonuclease L
induction of a
protein kinase
ds RNA
activated
protein kinase
ATP
ATP
phosphorylated initiation
factor (eIF-2)
2’5’oligo A
mRNA degraded
inhibition of protein synthesis
24
interferons
• only made when needed
25
OTHER EFFECTS OF
INTERFERONS
• ALL TYPES
– INCREASE MHC I EXPRESSION
• CYTOTOXIC T-CELLS
– ACTIVATE NK CELLS
• CAN KILL VIRALLY INFECTED CELLS
26
OTHER EFFECTS OF
INTERFERONS
• INTERFERON-GAMMA
– INCREASES MHC II EXPRESSION ON APC
• HELPER T-CELLS
– INCREASES ANTIVIRAL POTENTIAL OF
MACROPHAGES
• INTRINSIC
• EXTRINSIC
27
THERAPEUTIC USES OF
INTERFERONS
• ANTI-VIRAL
– e.g. interferon-alpha is currently approved for certain
cases of acute and chronic HCV and chronic HBV
• MACROPHAGE ACTIVATION
– interferon-gamma has been tried for e.g. lepromatous
leprosy, leishmaniasis, toxoplasmosis
• ANTI-TUMOR
– have been used in e.g. melanoma, Kaposi’s sarcoma,
CML
• MULTIPLE SCLEROSIS
– interferon-beta
28
Viral response to host immune
system
Viruses may :
block interferon binding
inhibit function of interferon-induced proteins
inhibit NK function
interfere with MHC I or MHC II expression
block complement activation
inhibit apoptosis
etc!
29
SIDE EFFECTS OF
INTERFERONS
•
•
•
•
FEVER
MALAISE
FATIGUE
MUSCLE PAINS
30
BACK TO INFLUENZA
31
PROTECTION AGAINST
RE-INFECTION
• IgG and IgA
– IgG less efficient but lasts longer
• antibodies to both HA and NA important
– antibody to HA more important (can
neutralize)
32
SYMPTOMS
•
•
•
•
•
•
FEVER
HEADACHE
MYALGIA
COUGH
RHINITIS
OCULAR SYMPTOMS
33
CLINICAL FINDINGS
• SEVERITY
– VERY YOUNG
– ELDERLY
– IMMUNOCOMPROMISED
– HEART OR LUNG
DISEASE
34
PULMONARY
COMPLICATIONS
• CROUP (YOUNG CHILDREN)
• PRIMARY INFLUENZA VIRUS
PNEUMONIA
• SECONDARY BACTERIAL INFECTION
– Streptococcus pneumoniae
– Staphlyococcus aureus
– Hemophilus influenzae
35
NON-PULMONARY
COMPLICATIONS
• myositis (rare, > in children, > with type B)
• cardiac complications
• recent studies report encephalopathy
– studies of patients <21 yrs in Michigan - 8 cases seen
last season
• liver and CNS
– Reye syndrome
• peripheral nervous system
– Guillian-Barré syndrome
36
Reye’s syndrome
•
•
•
•
liver - fatty deposits
brain - edema
vomiting, lethargy, coma
risk factors
– youth
– certain viral infections (influenza, chicken
pox)
– aspirin
37
NON-PULMONARY
COMPLICATIONS
•
•
•
•
myositis (rare, > in children, > in type B)
cardiac complications
encephalopathy
liver and CNS
– Reye’s syndrome
• peripheral nervous system
– Guillian-Barré syndrome
38
Guillian-Barré syndrome
• 1976/77 swine flu vaccine
– 35,000,000 doses
• 354 cases of GBS
• 28 GBS-associated deaths
• recent vaccines much lower risk
39
MORTALITY
• MAJOR CAUSES OF INFLUENZA
VIRUS- ASSOCIATED DEATH
– BACTERIAL PNEUMONIA
– CARDIAC FAILURE
• 90% OF DEATHS IN THOSE OVER 65
YEARS OF AGE
40
DIAGNOSIS
• ISOLATION
– NOSE, THROAT SWAB
– TISSUE CULTURE OR EGGS
• SEROLOGY
• RAPID TESTS
• provisional - clinical picture + outbreak
41
HA protein - attachment, fusion
S
S
S
S
S
S
cell enzymes
acid pH
42
NA protein - neuraminidase
43
ANTIGENIC DRIFT
• HA and NA accumulate mutations
– RNA virus
• immune response no longer protects
fully
• sporadic outbreaks, limited epidemics
44
ANTIGENIC SHIFT
• “new” HA or NA proteins
• pre-existing antibodies do not protect
• may get pandemics
45
INFLUENZA A PANDEMICS
Ryan et al., in Sherris Medical Microbiology
46
where do “new” HA and NA
come from?
• 13 types HA
• 9 types NA
– all circulate in birds
• pigs
– avian and human
47
where do “new” HA and NA
come from?
48
why do we not have influenza
B pandemics?
• so far no shifts
have been
recorded
• no animal
reservoir
known
49
SURVEILLANCE
50
CDC/Katherine Lord
actual percentage of deaths
(CDC MMWR 2003 / Vol. 52 / No. RR-8)
51
100
90
80
70
60
50
40
30
20
10
0
H1N1
H3N2
B
99/00
00/01
01/02
02/03
52
VACCINE
• ‘BEST GUESS’ OF MAIN ANTIGENIC
TYPES
– CURRENTLY
•
•
•
•
type A - H1N1
type A - H3N2
type B
each year choose which variant of each
subtype is the best to use for optimal protection
53
VACCINE
• inactivated
• egg grown
• sub-unit vaccine for children
• reassortant live vaccine approved 2003
– for healthy persons (those not at risk for
complications from influenza infection)
ages 5-49 years
54
CDC
55
RECOMMENDATIONS
Persons at High Risk for Influenza-Related Complications
· $ 65 years
· residents of nursing homes and other chronic-care facilities
· adults/children who have chronic pulmonary or cardiovascular
disorders, including asthma
· adults/children who have required regular medical follow-up or
hospitalization during the last year because of chronic metabolic
diseases (including diabetes mellitus), renal dysfunction,
hemoglobinopathies, or immunosuppression (including
immunosuppression caused by medications)
56
RECOMMENDATIONS
Persons at High Risk for Influenza-Related Complications
· children and teenagers (6 mths to 18 yrs) receiving long-term
aspirin therapy - might be at risk for developing Reye syndrome
after influenza
· women who will be in the 2nd or 3rd trimester of pregnancy
during the influenza season.
57
RECOMMENDATIONS
Persons aged 50-64 years
increased prevalence of high-risk conditions
from public health point of view, easier to target by age
than by high-risk condition (which may not have been
discovered)
58
RECOMMENDATIONS
Persons Who Can Transmit Influenza to Those at High
Risk
Persons who are clinically or subclinically infected can
transmit influenza virus to persons at high risk for
complications from influenza.
59
RECOMMENDATIONS
· physicians, nurses, and other personnel in both hospital and
outpatient-care settings
· employees of nursing homes and chronic-care facilities who
have contact with patients or residents
· employees of assisted living and other residences for persons
in high-risk groups
· persons who provide home care to persons in high-risk groups
· household members (including children) of persons in high-risk
groups.
60
RECOMMENDATIONS
Children from 0-23 mths are at increased risk for
hospitalization from influenza, vaccination is encouraged
for their household contacts and out-of-home caretakers,
particularly for contacts of children aged 0–5 months
because influenza vaccines have not been approved for
use among children aged <6 months.
61
RECOMMENDATIONS
• others, including travellers and the
general population may wish to be
vaccinated
62
PREVENTION - DRUGS
• RIMANTADINE
(M2)
• type A only
• AMANTADINE
(M2)
• type A only
• ZANAMIVIR
(NA)
• types A and B, not yet approved for prevention
• OSELTAMIVIR
(NA)
• types A and B
63
TREATMENT - DRUGS
• RIMANTADINE
(M2)
• type A only, needs to be given early
• AMANTADINE
(M2)
• type A only, needs to be given early
• ZANAMIVIR
(NA)
• types A and B, needs to be given early
• OSELTAMIVIR
(NA)
• types A and B, needs to be given early
64
NA protein - neuraminidase
.
.
.
.
.
. . .
.
.
..
...
.
.
.
.
65
OTHER TREATMENT
• REST, LIQUIDS, ANTI-FEBRILE
AGENTS (NO ASPIRIN FOR AGES
6MTHS-18YRS)
• BE AWARE OF COMPLICATIONS AND
TREAT APPROPRIATELY
66
severity of illness
animal reservoir
human pandemics
human epidemics
antigenic changes
segmented genome
amantadine, rimantidine
zanamivir
surface glycoproteins
TYPE A
TYPE B
TYPE C
++++
yes
yes
yes
shift, drift
yes
sensitive
sensitive
2
++
no
no
yes
drift
yes
no effect
sensitive
2
+
no
no
no (sporadic)
drift
yes
no effect
(1)
67
END
68
live vaccine development
69
adapted from
Treanor JJ Infect. Med. 15:714
70